Collagen is the major extracellular structural protein in skin, tendon, bone, cartilage, and connective tissue in vertebrates. Collagen fibrils form a structural matrix that binds groups of cells together to form tissues. Collagen constitutes about 40 percent of all proteins in the body. Once collagen fibers are formed, they are not renewed. Thus, although these fibers undergo certain changes as skin, muscles, bones, joints, blood vessels, etc. experience natural processes such as aging; these altered collagen fibrils are not repaired or replaced.
Collagen disease is any one of a group of pathological conditions that are clinically distinct and of various etiologies. They cause in common, however, wide spread and systemic pathologic changes in connective tissue formed by collagen. Such diseases include lupus erythematosus, dermatomyositis, scleroderma, polyarteritis nodosa, thrombotic purpura, rheumatic fever, and rheumatoid arthritis. Collagen pathology may be mediated by collagenase, an enzyme that degrades collagen.
Collagen exists in vivo in the form of a polypeptide chain composed of three helical subunits wound about a common axis. These molecules polymerize into insoluble fibrils, and exist in tissue in this form. The helical structure is resistant to attack by proteolytic, or digestive, enzymes that degrade less-resistant proteins. There are, however, natural enzymes including animal collagenases which are capable of cleaving and thereby breaking down collagen molecules.
It has been shown, for example, that collagenase is responsible for ulcers appearing after the eye has been burned with alkali; collagen comprises the major organic component of the cornea. Similarly, this relationship exists for other ulcerative conditions of the cornea, including viral ulcers, such as herpes simplex, vaccinia; bacterial ulcers; degenerative ulcers and ulcers of unknown origin.
In mammals, collagenase is one of the key enzymes involved in the joint and cartilage destruction of rheumatoid arthritis; see for example, Arthritis And Rheumatism, 20 (6): 1231 (1977). The action of mammalian collagenase has also been implicated as a causative factor in several other diseases in mammals. These diseases include periodontal disease, tumor invasiveness, and epidermolysis bullosa; see for example, American Journal of Pathology, 92 (2): 509 (1978) and The New England Journal of Medicine, 291(13):652 (1974).
Certain of the collagen disorders are bacterially mediated. Corneal melting during bacterial infections is believed to be caused, in part or in whole, by the digestion of corneal collagen due to bacterial collagenase. Current treatment involves the use of cysteine which is only a weak inhibitor of collagenase. Gangrene is commonly caused by Clostridium and bacterial collagenase is thought to be important in the progression and consequences of this infection. Thus, pharmaceutical compositions effective to inhibit bacterial collagenase would be useful in preventing or ameliorating certain diseases.
Additionally, a standard laboratory technique involves the use of commercially-produced bacterial collagenase to prepare dispersions of cells separated from various minced tissue samples. The use of collagenase inhibitors in vitro is necessary to stop the action of collagenase once sufficient numbers of cells have been released into suspension. Also, affinity column chromatography using a bound collagenase inhibitor may be utilized in the purification of collagenase. Thus, effective collagenase inhibitors have several uses beyond that of clinical pharmacology.
Accordingly, collagenase inhibitors are generally useful in ameliorating or preventing pathological conditions in which collagenases play an etiological role.
U.S. Pat. No. 4,263,293 to Sundeen et al discloses a mammalian collagenase inhibitor having the general formula: ##STR3## wherein R.sub.1 is hydrogen, alkanoyl of 2 to 10 carbon atoms or arylcarbonyl; R.sub.2 is 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, or 4-alkyl-1-piperazinyl; R.sub.3 is alkyl of 3 to 8 carbon atoms, cycloalkyl, aryl, or arylalkyl; and n is an integer of 1 to 20. This patent discloses the use of certain compositions for the treatment of rheumatoid arthritis using these compounds, and provides methods for their preparation.
U.S. Pat. No. 4,361,574 to Grant et al also discloses a mammalian collagenase inhibitor in the form of a polyheterocyclic compound having the general formula: ##STR4## wherein R is hydrogen or lower alkyl, R.sub.1 is hydrogen, lower alkyl, lower alkoxy, trifluoromethyl or halo; and n is 1. These compounds and methods for their preparation are also disclosed in U.S. Pat. Nos. 4,214,089, and 3,704,239.
Certain ulcers and other pathologic conditions involving tissue destruction have been treated by the application of a collagenase inhibitor; such as, cysteine, acetyl cysteine, ethylene diamine tetraacetic acid (or its sodium or calcium salts) and heparin. As taught by U.S. Pat. No. 4,276,284 to Brown, applications repeated daily over a course of time are effective in preventing or reducing ulceration.
Thorsett et al in U.S. Pat. No. 4,316,896 disclose converting enzyme inhibitors and antihypertensive amino acid derivatives of the formula: ##STR5## wherein n is 0 or 1; R is hydrogen, lower alkyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, aminolower alkyl, guanidino lower alkyl, imidazoyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl, lower alkyl mercapto lower alkyl; R.sub.3 is hydrogen; R.sub.4 is hydrogen, lower alkyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, guanidino lower alkyl, imidazoyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl, lower alkyl mercapto lower alkyl; R.sub.3 and R.sub.4 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms or an alkylene bridge of from 2 to 3 carbon atoms and one sulfur atom; X is 0, NR.sup.5, S where R.sub.5 .dbd.H or lower alkyl; R.sub.1 is hydrogen, lower alkyl, aralkyl or aryl; and R.sub.2 is hydrogen, lower alkyl, aralkyl or aryl and pharmaceutically acceptable salts thereof.
U.S. Pat. No. 4,379,146 to Greenlee et al discloses a substituted phosphonamide and related compounds useful as converting enzyme inhibitors and as antihypertensives. Compounds are disclosed of the general formula: ##STR6## wherein R.sub.1 is alkyl or substituted alkyl of C.sub.1 -C.sub.6 wherein the substituent is halo, amino, acylamino; aralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the aryl function is phenyl or naphthyl optionally substituted by halo or hydroxyl; or, heteroaralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the heteroaryl group can be indolyl or thienyl; R.sub.2 is H, lower alkyl of C.sub.1 -C.sub.4, aralkyl such as benzyl; R.sub.3 is lower alkyl of C.sub.1 -C.sub.6 optionally substituted by an amino group; R.sub.4 is H, lower alkyl of C.sub.1 -C.sub.6, aralkyl such as benzyl; and X is (CH.sub.2).sub.n wherein n is 1 or 2, CH--OCH.sub.3, CH--OH, or S. Other phosphonamides are taught by U.S. Pat. Nos. 4,100,275; 4,143,134; and 4,316,896.